tbuckley/cabot-search huggingface dataset:
Extracellular vesicle-guided in situ reprogramming of synovial macrophages for the treatment of rheumatoid arthritis
Authors: Hyosuk Kim, Ji Hyun Back, Geonhee Han, Su Jin Lee, Yae Eun Park, Man Bock Gu, Yoosoo Yang, Ji Eun Lee, Sun Hwa Kim
Journal: Biomaterials (2022)

Activation state of synovial macrophages is significantly correlated with disease activity and severity of rheumatoid arthritis (RA) and provides valuable clues for RA treatment. Classically activated M1 macrophages in inflamed synovial joints secrete high levels of pro-inflammatory cytokines and chemokines, resulting in bone erosion and cartilage degradation. Herein, we propose extracellular vesicle (EV)-guided in situ macrophage reprogramming toward anti-inflammatory M2 macrophages as a novel RA treatment modality based on the immunotherapeutic concept of reestablishing M1-M2 macrophage equilibrium in synovial tissue. M2 macrophage-derived EVs (M2-EVs) were able to convert activated M1 into reprogrammed M2 (RM2) macrophages with extremely high efficiency (>90%), producing a distinct protein expression pattern characteristic of anti-inflammatory M2 macrophages. In particular, M2-EVs were enriched for proteins known to be involved in the generation and migration of M2 macrophages as well as macrophage reprogramming factors, allowing for rapid and efficient driving of macrophage polarization toward M2 phenotype. After administration of M2-EVs into the joint of a collagen-induced arthritis mouse model, the synovial macrophage polarization was significantly shifted from M1 to M2 phenotype, a process that benefited greatly from the long residence time (>3 days) of M2-EVs in the joint. This superb in situ macrophage-reprogramming ability of EVs resulted in decreased joint swelling, arthritic index score and synovial inflammation, with corresponding reductions in bone erosion and articular cartilage damage and no systemic toxicity. The anti-RA effects of M2-EVs were comparable to those of the conventional disease-modifying antirheumatic drug, Methotrexate, which causes a range of toxic adverse effects, including gastrointestinal mucosal injury. Overall, our EV-guided reprogramming strategy for in situ tuning of macrophage responses holds great promise for the development of anti-inflammatory therapeutics for the treatment of various inflammatory diseases in addition to RA.
Celastrol mitigates inflammation in sepsis by inhibiting the PKM2-dependent Warburg effect
Authors: Piao Luo, Qian Zhang, Tian-Yu Zhong, Jia-Yun Chen, Jun-Zhe Zhang, Ya Tian, Liu-Hai Zheng, Fan Yang, Ling-Yun Dai, Chang Zou, Zhi-Jie Li, Jing-Hua Liu, Ji-Gang Wang
Journal: Military Medical Research (2022)

Abstract Background Sepsis involves life-threatening organ dysfunction and is caused by a dysregulated host response to infection. No specific therapies against sepsis have been reported. Celastrol (Cel) is a natural anti-inflammatory compound that shows potential against systemic inflammatory diseases. This study aimed to investigate the pharmacological activity and molecular mechanism of Cel in models of endotoxemia and sepsis. Methods We evaluated the anti-inflammatory efficacy of Cel against endotoxemia and sepsis in mice and macrophage cultures treated with lipopolysaccharide (LPS). We screened for potential protein targets of Cel using activity-based protein profiling (ABPP). Potential targets were validated using biophysical methods such as cellular thermal shift assays (CETSA) and surface plasmon resonance (SPR). Residues involved in Cel binding to target proteins were identified through point mutagenesis, and the functional effects of such binding were explored through gene knockdown. Results Cel protected mice from lethal endotoxemia and improved their survival with sepsis, and it significantly decreased the levels of pro-inflammatory cytokines in mice and macrophages treated with LPS ( P &lt; 0.05). Cel bound to Cys424 of pyruvate kinase M2 (PKM2), inhibiting the enzyme and thereby suppressing aerobic glycolysis (Warburg effect). Cel also bound to Cys106 in high mobility group box 1 (HMGB1) protein, reducing the secretion of inflammatory cytokine interleukin (IL)-1β. Cel bound to the Cys residues in lactate dehydrogenase A (LDHA). Conclusion Cel inhibits inflammation and the Warburg effect in sepsis via targeting PKM2 and HMGB1 protein.
Routine rescreening for latent tuberculosis has low utility in patients with chronic immune-mediated inflammatory diseases treated with biologics: A single-center, retrospective cohort study
Authors: Urmi Khanna, Joshua Gallop, Ariana Ellis, Jeffery Hu, Abdulaziz Galadari, Anokhi Saklecha, Steve M Gordon, M Elaine Husni, Florian Rieder, Anthony P Fernandez
Journal: Journal of the American Academy of Dermatology (2022)
Multifocal Intrahepatic Cholangiocarcinoma and Operative Management of Inoperable Disease
Authors: Clifford S. Cho
Journal: JAMA Surgery (2022)

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Selected Articles from This Issue
Journal: Clinical Cancer Research (2022)

Interleukin-15 (IL-15) regulates the generation, persistence, and differentiation of natural killer (NK) and CD8 T cells.To expand its role in cancer immunotherapy, Chen and colleagues designed a multitumor model treated with the combination of intratumoral anti-CD40, parenteral IL-15 and anti-PD-1.Anti-CD40 given intratumorally not only reduced dosing requirements and toxicity, but it also stimulated the antitumor activity of the distal tumors, suggestive of an abscopal effect.IL-15 with intratumoral anti-CD40 was additive/synergistic, and the inclusion of the anti-PD-1 was additive to the combination.Thus, this treatment shows promise for patients with solid tumors or resistance to anti-PD-1 therapy.
Increased relative proportions of advanced melanoma among veterans: A comparative analysis with the Surveillance, Epidemiology, and End Results registry
Authors: Michael S. Chang, Jennifer La, Nicole Trepanowski, David Cheng, John R. Bihn, Nhan Do, Mary Brophy, Nathanael R. Fillmore, Rebecca I. Hartman
Journal: Journal of the American Academy of Dermatology (2022)
Risk factors for lower bone mineral density in older adults with type 1 diabetes: a cross-sectional study
Authors: Ann V Schwartz, Jye-Yu C Backlund, Ian H de Boer, Mishaela R Rubin, Annette Barnie, Kaleigh Farrell, Victoria R Trapani, Naina Sinha Gregory, Amisha Wallia, Ionut Bebu, John M Lachin, Barbara H Braffett, Rose Gubitosi-Klug
Journal: The Lancet Diabetes & Endocrinology (2022)
Impact of Continuous Positive Airway Pressure on Postoperative Atrial Fibrillation in Patients with Obstructive Sleep Apnea Undergoing Coronary Artery Bypass Graft Surgery: An Exploratory Randomized Multicenter Study
Authors: Síntya T. Chalegre, Martinha M. Barros, Bianca P. G. Silva, Sofia F. Furlan, Sara Q. C. Giampá, Jeozadak N. Marques, Afonso L. T. Albuquerque, Verônica S. Monteiro, Luciano F. Drager, Rodrigo Pinto Pedrosa
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Impact of Continuous Positive Airway Pressure on Postoperative Atrial Fibrillation in Patients with Obstructive Sleep Apnea Undergoing Coronary Artery Bypass Graft Surgery: An Exploratory Randomized Multicenter Study." American Journal of Respiratory and Critical Care Medicine, 206(3), pp. 358–360
A Learning Health System Agenda for Organizational Approaches to Enhancing Occupational Well-being Among Clinicians
Authors: Lisa S. Rotenstein, Edward R. Melnick, Christine A. Sinsky
Journal: JAMA (2022)

With the goal of building the health care system back stronger in a postpandemic world, the next frontier is a learning health system-based research agenda that fully characterizes clinician well-being, its determinants, and the factors that can help alleviate it.
Rivaroxaban vs placebo for extended antithrombotic prophylaxis after laparoscopic surgery for colorectal cancer
Authors: Cecilia Becattini, Ugo Pace, Felice Pirozzi, Annibale Donini, Giampiero Avruscio, Fabio Rondelli, Michela Boncompagni, Damiano Chiari, Marco De Prizio, Adriana Visonà, Raffaele De Luca, Francesco Guerra, Andrea Muratore, Giuseppe Portale, Marco Milone, Giampaolo Castagnoli, Marc Righini, Jacopo Martellucci, Roberto Persiani, Stefania Frasson, Francesco Dentali, Paolo Delrio, Mauro Campanini, Gualberto Gussoni, Maria Cristina Vedovati, Giancarlo Agnelli
Journal: Blood (2022)

The clinical benefit of extended prophylaxis for venous thromboembolism (VTE) after laparoscopic surgery for cancer is unclear. The efficacy and safety of direct oral anticoagulants for this indication are unexplored. PROphylaxis of venous thromboembolism after LAParoscopic Surgery for colorectal cancer Study II (PROLAPS II) was a randomized, double-blind, placebo-controlled, investigator-initiated, superiority study aimed at assessing the efficacy and safety of extended prophylaxis with rivaroxaban after laparoscopic surgery for colorectal cancer. Consecutive patients who had laparoscopic surgery for colorectal cancer were randomized to receive rivaroxaban (10 mg once daily) or a placebo to be started at 7 ± 2 days after surgery and given for the subsequent 3 weeks. All patients received antithrombotic prophylaxis with low-molecular-weight heparin from surgery to randomization. The primary study outcome was the composite of symptomatic objectively confirmed VTE, asymptomatic ultrasonography-detected deep vein thrombosis (DVT), or VTE-related death at 28 ± 2 days after surgery. The primary safety outcome was major bleeding. Patient recruitment was prematurely closed due to study drug expiry after the inclusion of 582 of the 646 planned patients. A primary study outcome event occurred in 11 of 282 patients in the placebo group compared with 3 of 287 in the rivaroxaban group (3.9 vs 1.0%; odds ratio, 0.26; 95% confidence interval [CI], 0.07-0.94; log-rank P = .032). Major bleeding occurred in none of the patients in the placebo group and 2 patients in the rivaroxaban group (incidence rate 0.7%; 95% CI, 0-1.0). Oral rivaroxaban was more effective than placebo for extended prevention of VTE after laparoscopic surgery for colorectal cancer without an increase in major bleeding. This trial was registered at www.clinicaltrials.gov as #NCT03055026.
PP2 protects from keratin mutation–associated liver injury and filament disruption via SRC kinase inhibition in male but not female mice
Authors: Pei Li, Dhiman Maitra, Ning Kuo, Raymond Kwan, Yang Song, Weiliang Tang, Lu Chen, Qing Xie, Li Liu, M. Bishr Omary
Journal: Hepatology (2022)

Background and Aims: Hepatocyte keratin polypeptides 8/18 (K8/K18) are unique among intermediate filaments proteins (IFs) in that their mutation predisposes to, rather than causes, human disease. Mice that overexpress human K18 R90C manifest disrupted hepatocyte keratin filaments with hyperphosphorylated keratins and predisposition to Fas‐induced liver injury. We hypothesized that high‐throughput screening will identify compounds that protect the liver from mutation‐triggered predisposition to injury. Approach and Results: Using A549 cells transduced with a lentivirus K18 construct and high‐throughput screening, we identified the SRC‐family tyrosine kinases inhibitor, PP2, as a compound that reverses keratin filament disruption and protects from apoptotic cell death caused by K18 R90C mutation at this highly conserved arginine. PP2 also ameliorated Fas‐induced apoptosis and liver injury in male but not female K18 R90C mice. The PP2 male selectivity is due to its lower turnover in male versus female livers. Knockdown of SRC but not another kinase target of PP2, protein tyrosine kinase 6, in A549 cells abrogated the hepatoprotective effect of PP2. Phosphoproteomic analysis and validation showed that the protective effect of PP2 associates with Ser/Thr but not Tyr keratin hypophosphorylation, and differs from the sex‐independent effect of the Ser/Thr kinase inhibitor PKC412. Inhibition of RAF kinase, a downstream target of SRC, by vemurafenib had a similar protective effect to PP2 in A549 cells and male K18 R90C mice. Conclusions: PP2 protects, in a male‐selective manner, keratin mutation‐induced mouse liver injury by inhibiting SRC‐triggered downstream Ser/Thr phosphorylation of K8/K18, which is phenocopied by RAF kinase inhibitor vemurafenib. The PP2/vemurafenib‐associated findings, and their unique mechanisms of action, further support the potential role of select kinase inhibition as therapeutic opportunities for keratin and other IF‐associated human diseases.
Age Distribution of All-Cause Mortality Among Children Younger Than 5 Years in Low- and Middle-Income Countries
Authors: Omar Karlsson, Rockli Kim, Andreas Hasman, S. V. Subramanian
Journal: JAMA Network Open (2022)

Coverage of essential child health and nutrition interventions in low- and middle-income countries remains suboptimal. Adverse exposures, such as undernutrition and infections, are particularly harmful during the 1000 days from conception until 2 years of age.To investigate whether deaths in children younger than 5 years-which also reflect adverse exposures faced by children more broadly-are concentrated in the first 2 years after birth.This cross-sectional study used a synthetic cohort probability method with Demographic and Health Surveys and Multiple Indicator Cluster Surveys from 77 low- and middle-income countries, with the earliest survey starting data collection in March 2010 and the most recent survey ending data collection in December 2019. Participants included 2 827 515 children who were younger than 5 years at any point 10 years before survey. Data were analyzed from March 11 to 21, 2022.Share of deaths among children younger than 5 years occurring before 1 month, at 1 to 23 months, and at 24 to 59 months of age.Among the 2 827 515 children included in the analysis, 81.5% (95% CI, 81.0%-82.0%) of deaths occurred in the first 2 years after birth ranging from 63.7% (95% CI, 61.6%-65.7%) in Niger to 97.8% (95% CI, 85.9%-99.7%) in Albania. An estimated 18.5% (95% CI, 18.0%-19.0%) of child deaths occurred at 24 to 59 months of age. Countries with higher mortality rates among children younger than 5 years had a lower share of deaths occurring in the neonatal period.In this sample of 77 low- and middle-income countries, a large majority of deaths among children younger than 5 years occurred before 2 years of age in all countries among boys and girls and in households with the worst and best living standards. Research has highlighted perinatal complications, infections, and undernutrition as primary causes of death among children younger than 5 years. Therefore, coverage of interventions to reduce these adverse exposures should be ensured during pregnancy and the first 2 years after birth, which is also a crucial period for human development.
Targeted proteoform mapping uncovers specific Neurexin-3 variants required for dendritic inhibition
Authors: David Hauser, Katharina Behr, Kohtarou Konno, Dietmar Schreiner, Alexander Schmidt, Masahiko Watanabe, Josef Bischofberger, Peter Scheiffele
Journal: Neuron (2022)

The diversification of cell adhesion molecules by alternative splicing is proposed to underlie molecular codes for neuronal wiring. Transcriptomic approaches mapped detailed cell-type-specific mRNA splicing programs. However, it has been hard to probe the synapse-specific localization and function of the resulting protein splice isoforms, or "proteoforms," in vivo. We here apply a proteoform-centric workflow in mice to test the synapse-specific functions of the splice isoforms of the synaptic adhesion molecule Neurexin-3 (NRXN3). We uncover a major proteoform, NRXN3 AS5, that is highly expressed in GABAergic interneurons and at dendrite-targeting GABAergic terminals. NRXN3 AS5 abundance significantly diverges from Nrxn3 mRNA distribution and is gated by translation-repressive elements. Nrxn3 AS5 isoform deletion results in a selective impairment of dendrite-targeting interneuron synapses in the dentate gyrus without affecting somatic inhibition or glutamatergic perforant-path synapses. This work establishes cell- and synapse-specific functions of a specific neurexin proteoform and highlights the importance of alternative splicing regulation for synapse specification.
Cluster analysis of transcriptomic datasets to identify endotypes of idiopathic pulmonary fibrosis
Authors: Luke M Kraven, Adam R Taylor, Philip L Molyneaux, Toby M Maher, John E McDonough, Marco Mura, Ivana V Yang, David A Schwartz, Yong Huang, Imre Noth, Shwu Fan Ma, Astrid J Yeo, William A Fahy, R Gisli Jenkins, Louise V Wain
Journal: Thorax (2022)

Background Considerable clinical heterogeneity in idiopathic pulmonary fibrosis (IPF) suggests the existence of multiple disease endotypes. Identifying these endotypes would improve our understanding of the pathogenesis of IPF and could allow for a biomarker-driven personalised medicine approach. We aimed to identify clinically distinct groups of patients with IPF that could represent distinct disease endotypes. Methods We co-normalised, pooled and clustered three publicly available blood transcriptomic datasets (total 220 IPF cases). We compared clinical traits across clusters and used gene enrichment analysis to identify biological pathways and processes that were over-represented among the genes that were differentially expressed across clusters. A gene-based classifier was developed and validated using three additional independent datasets (total 194 IPF cases). Findings We identified three clusters of patients with IPF with statistically significant differences in lung function (p=0.009) and mortality (p=0.009) between groups. Gene enrichment analysis implicated mitochondrial homeostasis, apoptosis, cell cycle and innate and adaptive immunity in the pathogenesis underlying these groups. We developed and validated a 13-gene cluster classifier that predicted mortality in IPF (high-risk clusters vs low-risk cluster: HR 4.25, 95% CI 2.14 to 8.46, p=3.7×10 −5 ). Interpretation We have identified blood gene expression signatures capable of discerning groups of patients with IPF with significant differences in survival. These clusters could be representative of distinct pathophysiological states, which would support the theory of multiple endotypes of IPF. Although more work must be done to confirm the existence of these endotypes, our classifier could be a useful tool in patient stratification and outcome prediction in IPF.
Protecting Children Against Omicron
Authors: Sophie E. Katz, Kathryn Edwards
Journal: JAMA (2022)

Katherine E. Fleming-Dutra, MD; Amadea Britton, MD; Nong Shang, PhD; Gordana Derado, PhD; Ruth Link-Gelles, PhD; Emma K. Accorsi, PhD; Zachary R. Smith, MA; Joseph Miller, PhD; Jennifer R. Verani, MD; Stephanie J. Schrag, DPhil
Long-Term Trends in Home Respiratory Medical Equipment among U.S. Medicare Patients, 2013–2019
Authors: Kevin I. Duan, Edwin S. Wong, Joshua M. Liao, Amber K. Sabbatini, David H. Au
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

"Long-Term Trends in Home Respiratory Medical Equipment among U.S. Medicare Patients, 2013–2019 ." American Journal of Respiratory and Critical Care Medicine, 206(4), pp. 509–511
Increased SARS-CoV-2 Infection, Protease, and Inflammatory Responses in Chronic Obstructive Pulmonary Disease Primary Bronchial Epithelial Cells Defined with Single-Cell RNA Sequencing
Authors: Matt D. Johansen, Rashad M. Mahbub, Sobia Idrees, Duc H. Nguyen, Stefan Miemczyk, Prabuddha Pathinayake, Kristy Nichol, Nicole G. Hansbro, Linden J. Gearing, Paul J. Hertzog, David Gallego-Ortega, Warwick J. Britton, Bernadette M. Saunders, Peter A. Wark, Alen Faiz, Philip M. Hansbro
Journal: American Journal of Respiratory and Critical Care Medicine (2022)

Patients with chronic obstructive pulmonary disease (COPD) develop more severe coronavirus disease (COVID-19); however, it is unclear whether they are more susceptible to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and what mechanisms are responsible for severe disease.
Clinical-Pathological Evaluation and Prognostic Analysis of 228 Merkel Cell Carcinomas Focusing on Tumor-Infiltrating Lymphocytes, MCPYV Infection and ALK Expression
Authors: Federica Santoro, Francesca Maletta, Renato Parente, Jessica Fissore, Cristian Tampieri, Leonardo Santoro, Nadia Birocco, Franco Picciotto, Pietro Quaglino, Marco Volante, Sofia Asioli, Rebecca Senetta, Mauro Papotti
Journal: Endocrine Pathology (2022)

Abstract Merkel cell carcinoma is a rare and aggressive primary neuroendocrine carcinoma of the skin, whose pathogenesis can be traced back to UV radiation damage or Merkel cell polyomavirus (MCPyV) infection. Despite some improvements on the characterization of the disease partly due to its increased incidence, crucial pathogenetic and prognostic factors still need to be refined. A consecutive series of 228 MCC from three hospitals in Turin was collected with the aim of both analyzing the apparent increase in MCC incidence in our area and investigating the distribution and prognostic role of clinical-pathological parameters, with a focus on MCPyV status, ALK tumor expression and tumor infiltrating lymphocytes (TILs). Review of morphology and conventional immunohistochemical staining was possible in 191 cases. In 50 cases, the expression of the novel neuroendocrine marker INSM1 was additionally assessed. Fourteen cases of MCC of unknown primary skin lesion were identified and separately analyzed. While confirming an exponential trend in MCC incidence in the last decades and providing a description of histological and cytological features of a large series of MCC, the present study concludes that 1) INSM1 is a highly sensitive marker in both skin and lymph node primary MCC; 2) positive MCPyV status, brisk TILs and lower tumor size and thickness are independent positive prognostic parameters, and the combination of the former two may provide a novel tool for prognostic stratification; 3) ALK is expressed 87% of MCC and associated with positive viral status, and could represent a prognostic biomarker, if validated in larger series.
Correction to: Enhancing the HSV-1-mediated antitumor immune response by suppressing Bach1
Authors: Chaohu Pan, Qiaomei Cai, Xiaorong Li, Lili Li, Liping Yang, Yu Chen, Junxiao Liu, Wancheng Liu, Meiling Gao, Tianqi Sui, Xiaoyang Wang, Huiming Fan, Jiayin Ruan, Yueyue Shi, Saihua Chen, Lucy S. Cheng, Jiayong Liu, Heng Yang, Genhong Cheng
Journal: Cellular and Molecular Immunology (2022)
Cesario's framework for understanding group disparities is radically incomplete
Authors: Morgan Weaving, Cordelia Fine
Journal: Behavioral and Brain Sciences (2022)

Abstract Cesario argues that experimental studies of bias tell us little about why group disparities exist. We argue that Cesario's alternative approach implicitly frames understanding of group disparities as a false binary between “bias” and “group differences.” This, we suggest, will contribute little to our understanding of the complex dynamics that produce group disparities, and risks inappropriately rationalizing them.